Background Neutrophilic asthma (NA) is a severe, corticosteroid-resistant phenotype associated with neutrophil extracellular traps (NETs) formation and Th17/Treg imbalance. Cold exposure exacerbates NA progression, increasing the global clinical burden. Currently, combination therapy with corticosteroids is considered a viable approach. This study aimed to investigate the therapeutic potential and mechanisms of ginsenoside Rk2 (Rk2) combined with dexamethasone (DEX) against cold-stimulated neutrophilic asthma (CSNA). Methods A corticosteroid-resistant BEAS-2B cell model was established by NTHi stimulation. A CSNA mouse model was established via ovalbumin sensitization, NTHi infection, and cold stimulation, followed by Rk2 and/or DEX treatment. Airway hyperresponsiveness, histopathology, and neutrophil infiltration were measured to assess therapeutic efficacy. Th17/Treg populations were analyzed by flow cytometry. NETs formation was quantified in PMA-stimulated primary mouse neutrophils. A NETs-naïve CD4+ T cell co-culture system was used to examine the causal role of NETs in Th17/Treg imbalance. Transcriptomics and agonist-based gain-of-function experiments were conducted to validate the mechanism of Rk2 combined with DEX. Results Rk2 reversed DEX resistance by rebalancing GRα/GRβ, upregulating HDAC2, and promoting GRα nuclear translocation. Compared with monotherapy, Rk2 combined with DEX ameliorated airway inflammation and restored Th17/Treg homeostasis. Mechanistically, this combination therapy suppressed NETs formation by reducing NETs components, DNA release and ROS generation. NETs drove Th17/Treg imbalance via STAT1/NLRP3 inflammasome axis. Pharmacological activation of either STAT1 or NLRP3 reversed the beneficial effects. Conclusion Our findings demonstrate for the first time that Rk2, a potent natural corticosteroid potentiator, acts in combination with DEX to alleviate CSNA by suppressing the STAT1/NLRP3 inflammasome-NETs-Th17/Treg cascade.

BACKGROUND:Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by intestinal barrier dysfunction. Pseudoginsenoside RT2, an ocotillol-type ginsenoside widely present in Panax species, possesses unexplored therapeutic potential for UC. PURPOSE:This study investigated the efficacy of RT2 against UC and its mechanisms of intestinal barrier protection by driving epithelial renewal. METHODS:Anti‑UC effects of RT2 were assessed in lipopolysaccharide (LPS)‑stimulated Caco‑2 cells and dextran sulfate sodium (DSS)‑induced mice. Integrated transcriptomic and proteomic analyses were performed to identify key pathways in barrier restoration. Mechanistic validation was conducted using DSS‑induced intestinal organoids (encompassing all epithelial lineages) and LPS‑stimulated IEC-6 cells (non-transformed intestinal epithelial model). Effects on Wnt/β-catenin pathway were assessed with inhibitor ICG-001. RESULTS:In Caco‑2 cells, RT2 restored transepithelial electrical resistance (TEER), regulated cytokines and upregulated tight junction proteins (TJs). In UC mice, RT2 dose‑dependently ameliorated disease activity index (DAI), improved colon length and histopathology, increased anti‑inflammatory cytokines and reduced pro‑inflammatory cytokines. RT2 enhanced TJs and epithelial markers. Multi-omics analysis linked RT2's benefits to Wnt/β-catenin pathway activation. In organoids, RT2 increased budding and Lgr5 expression. In IEC‑6 cells, RT2 restored TEER, promoted proliferation/migration, suppressed apoptosis and upregulated TJs and epithelial markers. Mechanistically, RT2 facilitated Wnt ligand-receptor binding, leading GSK-3β phosphorylation, disassembly of the destruction complex and β-catenin nuclear translocation. All effects were abolished by ICG‑001. CONCLUSIONS:RT2 attenuates UC by activating Wnt/β‑catenin pathway, thereby restoring intestinal barrier integrity via driving epithelial renewal, with efficacy comparable to the positive control drug SASP. RT2 represents a promising natural product candidate for UC treatment.

ETHNOPHARMACOLOGICAL RELEVANCE:Panax ginseng C.A. Meyer has been used traditionally for treating gastrointestinal disorders. Oleanolic acid 28-O-β-D- glucopyranoside (OAG), a major pentacyclic triterpenoid in ginseng, has demonstrated the antioxidant and the anti-ulcerative colitis effects in our previous studies. However, whether OAG intervenes UC by alleviating oxidative stress injury through regulating ferroptosis remains unclear. AIM OF THE STUDY:To explore the underlying mechanism of OAG regulating ferroptosis to alleviate UC. MATERIALS AND METHODS:A TNBS-induced UC rat model, which closely mimics the immunological characteristics of human UC, was established to evaluate the therapeutic efficacy of OAG by analyzing the disease activity index (DAI), colonic macroscopic damage index (CMDI), biochemical indicators, Th17/Treg cell ratio and IL-17 levels, pathomorphological alterations, tight junction proteins (TJs), intestinal epithelial ultrastructure. Subsequently, an integrated multi-omics analysis was conducted to elucidate whether ferroptosis pathways underlie OAG's efficacy against UC and to screen for key candidate genes and proteins, which were further validated using quantitative PCR and western blotting. Finally, molecular docking and the cellular thermal shift assay were performed to confirm the direct binding of OAG to key ferroptosis-related proteins in an RSL3-induced ferroptosis model of Caco-2 cells. RESULTS:OAG treatment significantly ameliorated UC symptoms, attenuated oxidative stress and inflammatory cell infiltration, reduced Th17/Treg cell ratio and IL-17 levels, and enhanced intestinal epithelial barrier integrity. Ferroptosis inhibition was identified as the crucial mechanism mediating OAG's therapeutic effects, with direct interactions between OAG and key ferroptosis-related proteins (GPX4, NRF2, HO-1, and x-CT) executing its protective effects against UC. CONCLUSIONS:This study demonstrates that OAG effectively ameliorates TNBS- induced UC by modulating Nrf2/x-CT/GPX4-mediated ferroptosis pathway, furthering our understanding of its molecular mechanism and supporting its therapeutic potential for UC treatment.

[Objective] To establish an androgenic alopecia model in C57BL/6 mice, observe the improvement effect of Black Ginseng extract on alopecia, and explore its mechanism using network pharmacology and molecular docking methods. [Methods] An androgenic alopecia model was established by subcutaneous injection of testosterone propionate in mice. Different doses of Black Ginseng extract groups were set up and compared with Minoxidil. The improvement effect of Black Ginseng extract on androgenic alopecia was evaluated based on hair growth, dermal thickness, hair follicle morphology and count, serum hormone levels, and skin tissue VEGF and TGF-β content. Based on previous studies, the chemical constituents of Black Ginseng extract were identified. Swiss Target Prediction and Symmap databases were used to obtain targets of Black Ginseng’s chemical constituents, combined with alopecia-related targets from Malacard, DisGeNET, and Genecards databases to construct a "Black Ginseng-chemical composition-intersection target-alopecia" interaction network, screening key chemical components and targets, followed by molecular docking analysis. [Results] Mice in the Black Ginseng extract groups showed better hair growth than the model group, with increased dermal thickness, decreased serum testosterone and dihydrotestosterone levels, increased estradiol levels, increased VEGF expression, and decreased TGF-β expression in skin, all in a dose-dependent manner. Key chemical components Deoxyoleanolic acid, Ginsenoside Rb1, Ginsenoside Rg3, Ginsenoside Rh4, and Campesterol, as well as key targets INS, AR, VEGFA, PPARG, LEP, and CASP3, were identified. Molecular docking results showed stable binding between key components and targets. [Conclusion] Black Ginseng extract improves androgen-induced alopecia in mice, likely by regulating targets such as AR and pathways like MAPK. This provides a scientific basis for further research and development of Black Ginseng.

This review covers the structures of diterpenoids, including chain (72), monocyclic (9), labdane-type (67), clerodane-type (127) abietane-type (716), (ent)-kaurane-type (89), grayanane-type (331), ingenane-type (55), tigliane-type (154), daphnane-type (237), and aconitine-type diterpene alkaloids (265) with rich biological activities reported in 2013–2023. And the drugs in clinical use or under clinical investigation of diterpenoids and leading compounds were summarized.

Steroid-resistant asthma (SRA), resisting glucocorticoids such as dexamethasone (DEX), is a bottleneck in the treatment of asthma. It is characterized by a predominantly neutrophilic inflammatory subtype and is prone to developing into severe refractory asthma and fatal asthma. Currently, there is a lack of universally effective treatments for SRA. Moreover, since cold stimulation does increase the risk of asthma development and exacerbate asthma symptoms, the treatment of cold-stimulated SRA (CSRA) will face greater challenges. To find effective new methods to ameliorate CSRA, this study established a CSRA mouse model of allergic airway inflammation mimicking human asthma for the first time and evaluated the alleviating effects of 80% ethanol extract of mountain-cultivated ginseng (MCG) based on multi-omics analysis. The results indicate that cold stimulation indeed exacerbated the SRA-related symptoms in mice; the DEX individual treatment did not show a satisfactory effect; while the combination treatment of DEX and MCG could dose-dependently significantly enhance the lung function; reduce neutrophil aggregation; decrease the levels of LPS, IFN-γ, IL-1β, CXCL8, and IL-17; increase the level of IL-10; alleviate the inflammatory infiltration; and decrease the mucus secretion and the expression of MUC5AC. Moreover, the combination of DEX and high-dose (200 mg/kg) MCG could significantly increase the levels of tight junction proteins (TJs), regulate the disordered intestinal flora, increase the content of short-chain fatty acids (SCFAs), and regulate the abnormal gene profile and metabolic profile. Multi-omics integrated analysis showed that 7 gut microbes, 34 genes, 6 metabolites, and the involved 15 metabolic/signaling pathways were closely related to the pharmacological effects of combination therapy. In conclusion, integrated multi-omics profiling highlighted the benefits of MCG for CSRA mice by modulating the interactions of microbiota, genes, and metabolites. MCG shows great potential as a functional food in the adjuvant treatment of CSRA.

The purpose of this study was to explore the therapeutic effect of the oral administration of pseudo-ginsenoside RT4 (RT4) on ulcerative colitis (UC), and to determine the rate of absorption and distribution of RT4 in mice with UC. Balb/c mice were induced using dextran sulfate sodium salts (DSS) to establish the UC model, and 10, 20, or 40 mg/kg of RT4 was subsequently administered via gavage. The clinical symptoms, inflammatory response, intestinal barrier, content of total short-chain fatty acids (SCFAs), and gut microbiota were investigated. Caco-2 cells were induced to establish the epithelial barrier damage model using LPS, and an intervention was performed using 4, 8, and 16 µg/mL of RT4. The inflammatory factors, transient electrical resistance (TEER), and tight-junction protein expression were determined. Finally, pharmacokinetic and tissue distribution studies following the intragastric administration of RT4 in UC mice were performed. According to the results in mice, RT4 decreased the disease activity index (DAI) score, restored the colon length, reduced the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), and boosted the levels of immunosuppressive cytokine IL-10, increased the content of SCFAs, improved the colonic histopathology, maintained the ultrastructure of colonic mucosal epithelial cells, and corrected disturbances in the intestinal microbiota. Based on the results in caco-2 cells, RT4 reduced the levels of TNF-α, IL-6, and IL-1β; protected integrity of monolayers; and increased tight-junction protein expression. Additionally, the main pharmacokinetic parameters (Cmax, Tmax, t1/2, Vd, CL, AUC) were obtained, the absolute bioavailability was calculated as 18.90% ± 2.70%, and the main distribution tissues were the small intestine and colon. In conclusion, RT4, with the features of slow elimination and directional distribution, could alleviate UC by inhibiting inflammatory factors, repairing the intestinal mucosal barrier, boosting the dominant intestinal microflora, and modulating the expression of SCFAs.

Ulcerative colitis (UC), an incurable and recurrent inflammatory bowel disease, presents a significant threat to health and highlights the need for novel therapeutic strategies. Oleanolic acid 28-O-β-D-glucopyranoside (OAG) is a naturally occurring pentacyclic triterpenoid found in ginseng. In this study, we demonstrated that OAG exhibited remarkable anti-UC activity in LPS-induced Caco-2 cells and DSS-induced model mice. First, OAG alleviated the symptoms of UC by mitigating weight loss, reducing the DAI score, and increasing colon length. Second, the inflammatory response was inhibited after OAG intervention, evidenced decreases in the spleen coefficient, cytokine levels, and inflammatory cell infiltration in colon tissue. Thirdly, OAG also enhanced intestinal epithelial barrier function, as evidenced by elevated TEER values, increased expression of tight junction proteins, diminished bacterial translocation, and maintained intact ultrastructure of colonic mucosal cells. Notably, compared with 5-aminosalicylic acid, OAG demonstrated superior efficacy in enhancing mucosal barrier function. Fourth, OAG increased microbial diversity, promoted the abundance of beneficial bacteria, reduced the abundance of harmful bacteria, and rebalanced the gut microbiome. Finally, the PI3K-AKT and MAPK signaling pathways were identified as crucial mechanisms underlying the therapeutic effects of OAG against UC through multi-omics. In summary, we identified OAG as a novel therapeutic agent against UC, demonstrating anti-inflammatory, barrier-preserving, and gut microbiota-modulating effects, highlighting its promising potential as a candidate UC drug.

Background: (-)-Syringaresinol (SYR), a natural lignan with significant antioxidant and anti-inflammatory activities, possesses various pharmacological benefits including cardio-protective, antibacterial, anticancer, and anti-aging effects. It was shown that the effectiveness of (+)-syringaresinol diglucoside on the ulcerative colitis (UC) was attributed to the active metabolite (+)-syringaresinol (the enantiomor of SYR). However, the efficacy of SYR against UC remains unclear, and the associated molecular mechanism has not been revealed yet Purpose: This study aimed to assess the protective effect of SYR in UC and its underlying mechanism Study design and methods: We examined SYR's protective impact on the intestinal epithelial barrier and its ability to inhibit inflammatory responses in both a lipopolysaccharide (LPS)-induced Caco-2 cell model and a dextran sodium sulfate (DSS)-induced UC mouse model. We also explored the potential signaling pathways regulated by SYR using transcriptome analysis and western blot assay Results: In Caco-2 cells, SYR significantly increased trans-epithelial electrical resistance, reduced tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL -6), interferon-gamma (IFN-gamma), and cyclooxygenase-2 (COX -2) levels, and enhanced cellular tight junction protein expression and distribution. In mice with UC, oral treatment with SYR (10, 20, 40 mg.kg(-1)) dose-dependently increased body weight, colon length, and expression of tight junction proteins, decreased disease activity index score, spleen coefficient, cytokine serum levels, bacterial translocation, and intestinal damage, and also preserved the ultrastructure of colonic mucosal cells. Transcriptomics indicated that the anti-UC effect of SYR is mediated via the PI3K-Akt/MAPK/Wnt signaling pathway. Conclusion: In summary, SYR effectively mitigated the development of UC by enhancing the intestinal epithelial barrier function and attenuating the inflammatory response. The plant-derived product SYR might be a potentially effective therapeutical agent against UC.

Saponins, the major bioactive components of Panax ginseng C. A. Mey. (Renshen in Chinese), are gradually emerging as research hotspots owing to the possession of various pharmacological activities. This review updates the ginsenosides list from P. ginseng and the steam-processed ginseng (red ginseng and black ginseng) up to 271 by June of 2024, encompassing 241 saponins from different parts of P. ginseng (roots, stems, leaves, flowers, berries, and seeds), 103 from red ginseng, and 65 from black ginseng, respectively. Among 271 saponins, there are a total of 249 (1−249) dammarane type (with a−z subtypes) tetracyclic triterpene saponins reported from each part of P. ginseng and steam-processed ginseng, two (250−251) lanostane type tetracyclic triterpene saponins identified from red ginseng, 18 (252−269) oleanane type pentacyclic triterpenoid saponins discovered from each part of P. ginseng and steam-processed ginseng, and two (270−271) ursane type pentacyclic triterpenoid saponins reported from red ginseng. Overall, this review expounds on the chemical diversity of ginsenosides in multiple aspects, such as chemical structure, spatial distribution and subtype comparison, processed products, and transformation. This facilitates more in-depth research on ginsenosides and contributes to the future development of ginseng.

Pseudoginsenoside DQ (PDQ), an ocotillol-type ginsenoside, is synthesized with protopanaxadiol through oxidative cyclization. PDQ exhibits good anti-arrhythmia activity. However, the inhibitory effect of PDQ on the cytochrome 450 (CYP450) enzymes and major drug transporters is still unclear. Inhibition of CYP450 and drug transporters may affect the efficacy of the drugs being used together with PDQ. These potential drug–drug interactions (DDIs) are essential for the clinical usage of drugs. In this study, we investigated the inhibitory effect of PDQ on seven CYP450 enzymes and seven drug transporters with in vitro models. PDQ has a significant inhibitory effect on CYP2C19 and P-glycoprotein (P-gp) with a half-inhibitory concentration (IC50) of 0.698 and 0.41 μM, respectively. The inhibition of CYP3A4 and breast cancer-resistant protein (BCRP) is less potent, with IC50 equal to 2.02–6.79 and 1.08 μM, respectively.

In the original publication [...].

Stroke, one of the leading causes of disability and death worldwide, is a severe neurological disease that threatens human life. Protopanaxatriol (PPT), panaxatriol-type saponin aglycone, is a rare saponin that exists in Panax ginseng and Panax Noto-ginseng. In this study, we established an oxygen-glucose deprivation (OGD)-PC12 cell model and middle cerebral artery occlusion/reperfusion (MCAO/R) model to evaluate the neuroprotective effects of PPT in vitro and in vivo. In addition, metabolomics analysis was performed on rat plasma and brain tissue samples to find relevant biomarkers and metabolic pathways. The results showed that PPT could significantly regulate the levels of LDH, MDA, SOD, TNF-α and IL-6 factors in OGD-PC12 cells in vitro. PPT can reduce the neurological deficit score and infarct volume of brain tissue in rats, restore the integrity of the blood-brain barrier, reduce pathological damage, and regulate TNF-α, IL-1β, IL-6, MDA, and SOD factors. In addition, the results of metabolomics found that PPT can regulate 19 biomarkers involving five metabolic pathways, including amino acid metabolism, arachidonic acid metabolism, sphingolipid metabolism, and glycerophospholipid metabolism. Thus, it could be inferred that PPT might serve as a novel natural agent for MCAO/R treatment.

Triterpenoids, an important group of secondary metabolites, are widely distributed naturally in plants in a free form or in the form of glycosides or esters, including tetracyclic triterpenoids and pentacyclic triterpenoids. This chapter covers 1371 triterpenoids reported from Jan. 2018 to Apr. 2022. These compounds are derived from 293 plants and 34 fungi and one animal. The compounds have a wide range of pharmacologic effects such as antitumor, antiinflammatory, antibacterial, antiviral, antiparasitic, liver protection, neuroprotection, cardiovascular protection, and metabolic regulation. A total of 382 references are cited. These triterpenoids provide numerous lead compounds with novel structures and broad pharmacologic effects for the research and discovery of innovative drugs, with good application prospects.

人参系五加科人参属多年生草本植物,素有"百草之王"的美誉,为药食同源的珍贵药材与食材.人参的主要活性成分为人参皂苷,其中很多皂苷被证实具有良好的抗脑缺血作用.本文通过整理相关文献,对人参皂苷抗脑缺血的相关机制进行总结和分析,包括抗凋亡、抗氧化应激、抗炎、减轻兴奋性氨基酸毒性、影响Ca2+电流、神经修复及神经保护作用等,以期为人参皂苷与脑缺血的相关基础或临床研究提供理论参考.

Increasing studies have demonstrated that ginsenoside Rg3 (Rg3) plays an important role in the prevention and treatment of various diseases, including allergic lower airway inflammation such as asthma. To investigate the role of Rg3 in allergic upper airway disease, the effect and therapeutic mechanism of Rg3 in allergic rhinitis (AR) were studied. Ovalbumin-induced AR model mice were intragastrically administered with Rg3. Nasal symptoms, levels of IgE, IL-4, IL-5, IL-13, SOD and MDA in serum, and histopathological analysis of nasal mucosa were used to evaluate the effect of Rg3 on ameliorating AR in mice. Moreover, nasal mucosa samples from the normal control group, AR model group and high dosage of Rg3 were collected to perform omics analysis. The differentially expressed genes and significantly changed metabolites were screened based on transcriptomics and metabolomics analyses, respectively. Integrative analysis was further performed to confirm the hub genes, metabolites and pathways. After Rg3 intervention, the nasal symptoms and inflammatory infiltration were effectively improved, the levels of IgE, IL-4, IL-5, IL-13 and MDA were significantly reduced, and the level of SOD was obviously increased. The results of the qRT-PCR assay complemented the transcriptomic findings. Integrated analysis showed that Rg3 played an anti-AR role mainly by regulating the interaction network, which was constructed by 12 genes, 8 metabolites and 4 pathways. Our findings suggested that Rg3 had a therapeutic effect on ovalbumin-induced AR in mice by inhibiting inflammation development and reducing oxidative stress. The present study could provide a potential natural agent for the treatment of AR.

Background: Saussurea pulchella (SP) is a traditional medicinal plant that is widely used in folk medicine because of its diverse biological activities, particularly its anti-inflammatory effects. However, the alleviation effect of SP on ulcerative colitis (UC) has not yet been realized. Purpose: To investigate the chemical composition and therapeutic effect of SP extract against UC. Methods: First, qualitative and quantitative analysis of SP 75% ethanol extract was performed by UPLC-Q/TOF-MS. Second, a dextran sodium sulfate (DSS) model of UC mice was developed to study the effects of SP on the symptoms, inflammatory factors, oxidative stress indexes and colon histopathology. Third, an integration of network pharmacology with metabolomics was performed to investigate the key metabolites, biological targets and metabolisms closely related to the effect of SP. Results: From the SP ethanol extract, 149 compounds were identified qualitatively and 20 were determined quantitatively. The SP could dose-dependently decrease the DAI score, spleen coefficient and the levels of TNF-α, IL-6, iNOS, MPO and MDA; increase the colon length, GSH level and SOD activity; and protect the intestinal barrier in the UC mice. Moreover, 10 metabolite biomarkers,18 targets and 5 metabolisms were found to play crucial roles in the treatment of UC with SP. Conclusions: SP 75% ethanol extract could effectively alleviate the progression of UC and, therefore, could be classified as a novel natural treatment for UC.

The cultivation of ginseng in fields is time-consuming and labor-intensive. Thus, culturing adventitious ginseng root in vitro constitutes an effective approach to accumulating ginsenosides. In this study, we employed UPLC-QTOF-MS to analyze the composition of the cultured adventitious root (cAR) of ginseng, identifying 60 chemical ingredients. We also investigated the immunomodulatory effect of cAR extract using various mouse models. The results demonstrated that the cAR extract showed significant activity in enhancing the immune response in mice. The mechanism underlying the immunomodulatory effect of cAR was analyzed through network pharmacology analysis, revealing potential ‘key protein targets’, namely TNF, AKT1, IL-6, VEGFA, and IL-1β, affected by potential ‘key components’, namely the ginsenosides PPT, F1, Rh2, CK, and 20(S)-Rg3. The signaling pathways PI3K–Akt, AGE–RAGE, and MAPK may play a vital role in this process.

Periodontitis is an inflammatory disease, mainly caused by the formation of a subgingival plaque biofilm. In recent years, growing attention has been paid to immunotherapy in the treatment of periodontitis, and the importance of communal intervention associated with macrophage polarization was emphasized. Herein, resveratrol (RES) and 20(S)-protopanaxadiol (PPD) were successfully self-assembled into RES@PPD nanoparticles (NPs) by the phenolic resin reaction. RES@PPD NPs have good stability and biocompatibility. The combined application of PPD and RES enhances the anti-inflammatory and antioxidant properties of nanocomposites, remarkably reduces the level of reactive oxygen species, and finally realizes the coordinated regulation of host immunity in periodontitis. The detailed mechanism is as follows: RES@PPD NPs inhibit M1 polarization of macrophages, promote M2 polarization by scavenging ROS, and then inhibit the NF-κB signalling pathway to regulate host immunity. In the animal model of periodontitis, RES@PPD NPs can remarkably decrease the level of pro-inflammatory cytokines, up-regulate the anti-inflammatory cytokines, and exhibit a profound therapeutic effect on local inflammation. Therefore, RES@PPD NPs are effective in antioxidation and anti-inflammation, thus providing a promising candidate drug for the treatment of periodontitis.